tbuckley/cabot-search huggingface dataset:
Cancer immunotherapy with enveloped self-amplifying mRNA CARG-2020 that modulates IL-12, IL-17 and PD-L1 pathways to prevent tumor recurrence
Authors: Ju Chen, Bhaskara Reddy Madina, Elham Ahmadi, Timur Olegovich Yarovinsky, Marie Marthe Krady, Eileen Victoria Meehan, Isabella China Wang, Xiaoyang Ye, Elise Pitmon, Xian-Yong Ma, Bijan Almassian, Valerian Nakaar, Kepeng Wang
Journal: Acta Pharmaceutica Sinica B (2023)

Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here we describe the application of virus-like vesicles (VLV) for delivery of three immunomodulators alone and in combination, as a promising approach for cancer immunotherapy. VLV vectors were designed to deliver single chain interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA) as a single payload or as the combination payload. Intralesional delivery of the VLV vector expressing IL-12 alone as well as the trivalent vector (designated CARG-2020) eradicated large established tumors. However, only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice, indicating a benefit of the combined immunomodulation. The abscopal effects of CARG-2020 on the non-injected contralateral tumors, as well as protection from the tumor cell re-challenge, suggest immune-mediated mechanism of protection and establishment of immunological memory. Mechanistically, CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting inflammation. The ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.
pH-Responsive polymer boosts cytosolic siRNA release for retinal neovascularization therapy
Authors: Shuai Guo, Chunhui Li, Changrong Wang, Xiaowen Cao, Xinyue Liu, Xing-Jie Liang, Yuanyu Huang, Yuhua Weng
Journal: Acta Pharmaceutica Sinica B (2023)

Small interfering RNA (siRNA) has a promising future in the treatment of ocular diseases due to its high efficiency, specificity, and low toxicity in inhibiting the expression of target genes and proteins. However, due to the unique anatomical structure of the eye and various barriers, delivering nucleic acids to the retina remains a significant challenge. In this study, we rationally design PACD, an A-B-C type non-viral vector copolymer composed of a hydrophilic PEG block (A), a siRNA binding block (B) and a pH-responsive block (C). PACDs can self-assemble into nanosized polymeric micelles that compact siRNAs into polyplexes through simple mixing. By evaluating its pH-responsive activity, gene silencing efficiency in retinal cells, intraocular distribution, and anti-angiogenesis therapy in a mouse model of hypoxia-induced angiogenesis, we demonstrate the efficiency and safety of PACD in delivering siRNA in the retina. We are surprised to discover that, the PACD/siRNA polyplexes exhibit remarkable intracellular endosomal escape efficiency, excellent gene silencing, and inhibit retinal angiogenesis. Our study provides design guidance for developing efficient nonviral ocular nucleic acid delivery systems.
Genome-wide meta-analysis implicates variation affecting mast cell biology in urticaria
Authors: Sheila Mary McSweeney, Jake Saklatvala, Rossella Rispoli, Clarisse Ganier, Grzegorz Woszczek, Laurent Thomas, Kristian Hveem, Mari Løset, Nick Dand, Christos Tziotzios, Michael Simpson, John Alexander McGrath
Journal: Journal of Allergy and Clinical Immunology (2023)

Urticaria is characterized by inappropriate mast cell degranulation leading to the development of wheals and/or angioedema. Twin and family studies indicate that there is a substantial heritable component to urticaria risk.
Unravelling of molecular biomarkers in synaptic plasticity of Alzheimer’s disease: Critical role of the restoration of neuronal circuits
Authors: None Pinky, None Neha, Mubashshir Ali, Prachi Tiwari, Mohammad Mumtaz Alam, Haroonrashid M. Hattiwale, Azfar Jamal, Suhel Parvez
Journal: Ageing Research Reviews (2023)
Multi-site, Multi-domain Airway Tree Modeling
Authors: Minghui Zhang, Yangqian Wu, Hanxiao Zhang, Yulei Qin, Hao Zheng, Wen Tang, Corey Arnold, Chenhao Pei, Pengxin Yu, Yang Nan, Guang Yang, Simon Walsh, Dominic C. Marshall, Matthieu Komorowski, Puyang Wang, Dazhou Guo, Dakai Jin, Ya’nan Wu, Shuiqing Zhao, Runsheng Chang, Boyu Zhang, Xing Lu, Abdul Qayyum, Moona Mazher, Qi Su, Yonghuang Wu, Ying’ao Liu, Yufei Zhu, Jiancheng Yang, Ashkan Pakzad, Bojidar Rangelov, Raul San Jose Estepar, Carlos Cano Espinosa, Jiayuan Sun, Guang-Zhong Yang, Yun Gu
Journal: Medical Image Analysis (2023)
Serum anti-tissue transglutaminase IgA and prediction of duodenal villous atrophy in adults with suspected coeliac disease without IgA deficiency (Bi.A.CeD): a multicentre, prospective cohort study
Authors: Carolina Ciacci, Julio Cesar Bai, Geoffrey Holmes, Abdulbaqi Al-Toma, Federico Biagi, Antonio Carroccio, Rachele Ciccocioppo, Antonio Di Sabatino, Rachel Gingold-Belfer, Mariana Jinga, Govind Makharia, Sonia Niveloni, Gary L Norman, Kamran Rostami, David S Sanders, Edgardo Smecuol, Vincenzo Villanacci, Santiago Vivas, Fabiana Zingone, Daniel Vasile Balaban, Patrizia Borgheresi, Pierpaolo Cavallo, Anna D'Odorico, Paola Iovino, Marco Vincenzo Lenti, Pasquale Mansueto, Ilaria Marsilio, Alina Popp, Vardit Shay, Martien van Wenum, Giovanni Zanoni
Journal: The Lancet. Gastroenterology & hepatology (2023)
Understanding and addressing the needs of people with cystic fibrosis in the era of CFTR modulator therapy
Authors: Katherine B Hisert, Susan E Birket, John Paul Clancy, Damian G Downey, John F Engelhardt, Isabelle Fajac, Robert D Gray, Marrah E Lachowicz-Scroggins, Nicole Mayer-Hamblett, Patrick Thibodeau, Katherine L Tuggle, Claire E Wainwright, Kris De Boeck
Journal: The Lancet Respiratory Medicine (2023)
Abstract 5467: Single-cell analysis of CD34-enriched blood cells reveals early prognostic markers of myelodysplastic syndromes
Authors: Eti Meiri, Nili Saar-Furer, Nimrod Rappoport, Sarah Pollock, Gila Lithwick-Yanai, Zohar Shipony, Nika Iremadze, Doron Lipson, Amos Tanay, Liran Shlush
Journal: Cancer Research (2023)

Abstract Myelodysplastic Syndromes (MDS) are a group of blood malignancies characterized by aberrant differentiation of hematopoietic stem and progenitor cells (HSPC) in the bone marrow that results in inefficient hematopoiesis and high risk of transformation to acute myeloid leukemia. In order to detect aberrant HSC differentiation in blood samples sensitively and accurately, we explored the use of scRNA-seq of CD34-enriched cells from peripheral blood in identifying differentiation trajectories that are abnormal in patient samples versus expected normal development. A total of 685,000 CD34-enriched PBMCs from 93 samples were analyzed using 10X 3’ v3 scRNA-seq library preparation. For increased efficiency, the samples were multiplexed in groups of 5 individuals and were later identified based on individual natural genetic variation using a custom genotyping assay or low-pass WGS. We then sequenced these 24 libraries on a UG100 sequencer to yield an average of 20,000 reads per cell. Six of these libraries were also sequenced on a NovaSeq. Comparison between scRNA profiles generated on the two different sequencers yielded highly similar results, including a similar ability to demultiplex the patient samples using genetic markers, accurately quantify gene modules and determine cell populations.To analyze the scRNA data, we used a novel computational framework, Metacell, to reconstruct metacell modules for both healthy and disease samples allowing us to find variability in the differentiation process between the disease samples and the normal baseline state. Two patients with MDS which had transformed to acute myelogenous leukemia (AML) demonstrated unique and distinct metacell clusters that were significantly separate from normal HSPC differentiation patterns, demonstrating distinct clusters with elevated levels of BCL2 which is an existing therapy target in secondary AML. Our results demonstrate that scRNA-seq analysis of peripheral blood HSPCs samples can be used to detect aberrations in HSC development in MDS patients and serve as a prognostic tool for stratification of patients with aggressive disease and drug response. Given the cost-efficiency of the entire process, we believe this is one of the first examples of the potential practical utility of single-cell analysis in a clinical setting. Citation Format: Eti Meiri, Nili Saar-Furer, Nimrod Rappoport, Sarah Pollock, Gila Lithwick-Yanai, Zohar Shipony, Nika Iremadze, Doron Lipson, Amos Tanay, Liran Shlush. Single-cell analysis of CD34-enriched blood cells reveals early prognostic markers of myelodysplastic syndromes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5467.
Effects of 2,3‐DPG knockout on SCD phenotype in Townes SCD model mice
Authors: Amey Barakat, Reema Jasuja, Lindsay Tomlinson, Zane Wenzel, Lila Ramaiah, Betty A. Petterson, Brendon Kapinos, Anagha Sawant, Vicente Pagan, Nathanael Lintner, Denise Field, Youngwook Ahn, Kelly M. Knee
Journal: American Journal of Hematology (2023)

Abstract Sickle cell disease (SCD) is a severe, multisystemic hematological disorder that impacts nearly every major organ in adults. The current approved treatments for SCD directly target mutant hemoglobin or address downstream disease pathology. Several compounds targeting reduction of 2,3‐DPG by activation of Pyruvate Kinase‐R are currently being evaluated in SCD patients. In this study, we genetically engineered a mouse lacking 2,3‐DPG on the Townes SCD mouse model background and evaluated the effects of 2,3‐DPG loss on disease pathology. Animals lacking 2,3‐DPG showed improvements in hematological markers and reductions in RBC sickling relative to native Townes mice, however, minimal difference in organ damage was observed in 2,3‐DPG deficient mice compared to native Townes animals. When animals lacking 2,3‐DPG were dosed with a compound designed to increase hemoglobin oxygen affinity, oxygen delivery related toxicity was observed.
Nuclear PARP1‐Targeted Photosensitizer as a Dual‐Mode DNA‐Damaging Agent and Immune Activator for Tumor Ablation
Authors: Peixia Li, Yayin Du, Jingru Qiu, Donghai Li, Guiling Li, Gang Shan
Journal: Advanced Healthcare Materials (2023)

Photodynamic therapy is a promising cancer therapeutic method that can damage DNA via photoinduced reactive oxygen species production. However, tumor cells can initiate DNA repair pathways to resist oxidative damage. In this study, a nuclear-targeted photosensitizer PARP-PS with a poly (ADP-ribose) polymerase 1 (PARP1) inhibitory effect is developed based on the reported PARP1 inhibitor, rucaparib. As a dual-mode DNA-damaging agent, PARP-PS damages DNA upon photoirradiation and enhances oxidative DNA damage by blocking the DNA repair pathway via PARP1 inhibition and degradation. Both in vitro and in vivo investigations demonstrate that PARP-PS exhibits high antitumor activity with few side effects in breast cancer. In addition, PARP-PS can act as an immunogenic cell death inducer to activate immune responses characterized by the promotion of cytotoxic T lymphocyte activation and tumor infiltration. Therefore, PARP-PS is a potential multimodal antitumor agent with synergistic phototherapeutic, chemotherapeutic, and immunotherapeutic effects.
HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor–Mutated Non–Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy
Authors: Helena A. Yu, Yasushi Goto, Hidetoshi Hayashi, Enriqueta Felip, James Chih-Hsin Yang, Martin Reck, Kiyotaka Yoh, Se-Hoon Lee, Luis Paz-Ares, Benjamin Besse, Paolo Bironzo, Dong-Wan Kim, Melissa L. Johnson, Yi-Long Wu, Thomas John, Steven Kao, Toshiyuki Kozuki, Erminia Massarelli, Jyoti Patel, Egbert Smit, Karen L. Reckamp, Qian Dong, Pomy Shrestha, Pang-Dian Fan, Parul Patel, Andrea Sporchia, David W. Sternberg, Dalila Sellami, Pasi A. Jänne
Journal: Journal of Clinical Oncology (2023)

Patritumab deruxtecan, or HER3-DXd, is an antibody-drug conjugate consisting of a fully human monoclonal antibody to human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. We assessed the efficacy and safety of HER3-DXd in patients with epidermal growth factor receptor (
Reply to Laura E. Davis, Adam Calaway, and Laura Bukavina’s Letter to the Editor re: Nima Nassiri, Giovanni Cacciamani, Inderbir S. Gill. Robotic Bladder Auto-transplantation in a Heart-beating Brain-dead Human Research Donor. Eur Urol. 2023;84:517–518
Authors: Nima Nassiri, Giovanni E. Cacciamani, Inderbir S. Gill
Journal: European Urology (2023)
Nanofiber Composite Microchannel‐Containing Injectable Hydrogels for Cartilage Tissue Regeneration
Authors: Jia Liu, Chen Tang, Jian Huang, Jinhong Gu, Jingbo Yin, Guohua Xu, Shifeng Yan
Journal: Advanced Healthcare Materials (2023)

Abstract Articular cartilage tissue is incapable of self‐repair and therapies for cartilage defects are still lacking. Injectable hydrogels have drawn much attention in the field of cartilage regeneration. Herein, the novel design of nanofiber composite microchannel‐containing hydrogels inspired by the tunnel‐piled structure of subway tunnels is proposed. Based on the aldehydized polyethylene glycol/carboxymethyl chitosan (APA/CMCS) hydrogels, thermosensitive gelatin microrods (GMs) are used as a pore‐forming agent, and coaxial electrospinning polylactic acid/gelatin fibers (PGFs) loaded with kartogenin (KGN) are used as a reinforcing agent and a drug delivery system to construct the nanofiber composite microchannel‐containing injectable hydrogels (APA/CMCS/KGN@PGF/GM hydrogels). The in situ formation, micromorphology and porosity, swelling and degradation, mechanical properties, self‐healing behavior, as well as drug release of the nanofiber composite microchannel‐containing hydrogels are investigated. The hydrogel exhibits good self‐healing ability, and the introduction of PGF nanofibers can significantly improve the mechanical properties. The drug delivery system can realize sustained release of KGN to match the process of cartilage repair. The microchannel structure effectively promotes bone marrow mesenchymal stem cell (BMSC) proliferation and ingrowth within the hydrogels. In vitro and animal experiments indicate that the APA/CMCS/KGN@PGF/GM hydrogels can enhance the chondrogenesis of BMSCs and promote neocartilage formation in the rabbit cartilage defect model.
Effect of Porosity and Pore Shape on the Mechanical and Biological Properties of Additively Manufactured Bone Scaffolds
Authors: Qingyang Liu, Fei Wei, Melanie Coathup, Wen Shen, Dazhong Wu
Journal: Advanced Healthcare Materials (2023)

This study investigates the effect of porosity and pore shape on the biological and mechanical behavior of additively manufactured scaffolds for bone tissue engineering (BTE). Polylactic acid scaffolds with varying porosity levels (15-78%) and pore shapes, including regular (rectangular pores), gyroid, and diamond (triply periodic minimal surfaces) structures, are fabricated by fused filament fabrication. Murine-derived macrophages and human bone marrow-derived mesenchymal stromal cells (hBMSCs) are seeded onto the scaffolds. The compressive behavior and surface morphology of the scaffolds are characterized. The results show that scaffolds with 15%, 30%, and 45% porosity display the highest rate of macrophage and hBMSC growth. Gyroid and diamond scaffolds exhibit a higher rate of macrophage proliferation, while diamond scaffolds exhibit a higher rate of hBMSC proliferation. Additionally, gyroid and diamond scaffolds exhibit better compressive behavior compared to regular scaffolds. Of particular note, diamond scaffolds have the highest compressive modulus and strength. Surface morphology characterization indicates that the surface roughness of diamond and gyroid scaffolds is greater than that of regular scaffolds at the same porosity level, which is beneficial for cell attachment and proliferation. This study provides valuable insights into porosity and pore shape selection for additively manufactured scaffolds in BTE.
Bioactive Suture with Added Innate Defense Functionality for the Reduction of Bacterial Infection and Inflammation
Authors: Manoj Puthia, Jitka Petrlova, Ganna Petruk, Marta Butrym, Firdaus Samsudin, Madelene Å Andersson, Ann‐Charlotte Strömdahl, Sebastian Wasserstrom, Erik Hartman, Sven Kjellström, Lucrezia Caselli, Oxana Klementieva, Peter J. Bond, Martin Malmsten, Deepak Bushan Raina, Artur Schmidtchen
Journal: Advanced Healthcare Materials (2023)

Surgical site infections (SSI) are a clinical and economic burden. Suture-associated SSI may develop when bacteria colonize the suture surface and form biofilms that are resistant to antibiotics. Thrombin-derived C-terminal peptide (TCP)-25 is a host defense peptide with a unique dual mode of action that can target both bacteria and the excessive inflammation induced by bacterial products. The peptide demonstrates therapeutic potential in preclinical in vivo wound infection models. In this study, the authors set out to explore whether TCP-25 can provide a new bioactive innate immune feature to hydrophilic polyglactin sutures (Vicryl). Using a combination of biochemical, biophysical, antibacterial, biofilm, and anti-inflammatory assays in vitro, in silico molecular modeling studies, along with experimental infection and inflammation models in mice, a proof-of-concept that TCP-25 can provide Vicryl sutures with a previously undisclosed host defense capacity, that enables targeting of bacteria, biofilms, and the accompanying inflammatory response, is shown.
Re: Mingxiao Feng, Andres Matoso, Gabriel Epstein, et al. Identification of Lineage-specific Transcriptional Factor-defined Molecular Subtypes in Small Cell Bladder Cancer. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2023.05.023
Authors: Kentaro Inamura
Journal: European Urology (2023)
Prime editor‐mediated functional reshaping of <i>ACE2</i> prevents the entry of multiple human coronaviruses, including SARS‐CoV‐2 variants
Authors: Wenwen Zhao, Jifang Li, Xiao Wang, Wei Xu, Bao‐Qing Gao, Jiangchao Xiang, Yaofeng Hou, Wei Liu, Jing Wu, Qilian Qi, Jia Wei, Xiaoyu Yang, Lu Lu, Li Yang, Jia Chen, Bei Yang
Journal: MedComm (2023)

The spike protein of SARS-CoV-2 hijacks the host angiotensin converting enzyme 2 (ACE2) to meditate its entry and is the primary target for vaccine development. Nevertheless, SARS-CoV-2 keeps evolving and the latest Omicron subvariants BQ.1 and XBB have gained exceptional immune evasion potential through mutations in their spike proteins, leading to sharply reduced efficacy of current spike-focused vaccines and therapeutics. Compared with the fast-evolving spike protein, targeting host ACE2 offers an alternative antiviral strategy that is more resistant to viral evolution and can even provide broad prevention against SARS-CoV and HCoV-NL63. Here, we use prime editor (PE) to precisely edit
How should good lung health be defined at the population and individual levels?
Authors: Joan B. Soriano, Christine Jenkins
Journal: European Respiratory Journal (2023)

Good lung health is a critical component of overall health and well-being. However, determining what constitutes good lung health can be challenging, as it depends on both population-level and individual-level factors. Surprisingly, to the best of our knowledge, good lung health has not been yet defined [1, 2]. Here we explore different ways of defining good lung health and suggest some practical approaches for promoting it. Rather than focusing on respiratory disease, a shift to lung health and wellness is worth exploring <https://bit.ly/3O7TQfi>
“Post tuberculosis”: the urgent need for inclusion of lung health outcomes in tuberculosis treatment trials
Authors: Anthony Byrne, Brian Allwood, Ingrid Schoeman, James Johnston, Gautam Kalyatanda, Goodman Makanda, Kevin Mortimer, Carole Mitnick, Rebecca Nightingale, Obianuju Ozoh, Andrea Rachow, Marieke Van Der Zalm
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>New TB treatment regimens are a welcome advancement. However, for the millions of TB survivors with impaired lung function and quality of life, more holistic outcome measures and the inclusion of lung function is essential in future TB treatment trials.</b>https://bit.ly/3PWT0o2
High-dose (40 mg)<i>versus</i>low-dose (20 mg) prednisolone for treating sarcoidosis: a randomised trial (SARCORT trial)
Authors: Sahajal Dhooria, Inderpaul Singh Sehgal, Ritesh Agarwal, Valliappan Muthu, Kuruswamy Thurai Prasad, Pooja Dogra, Uma Debi, Mandeep Garg, Amanjit Bal, Nalini Gupta, Ashutosh Nath Aggarwal
Journal: European Respiratory Journal (2023)

Background Current guidelines recommend 20–40 mg·day −1 of oral prednisolone for treating pulmonary sarcoidosis. Whether the higher dose (40 mg·day −1 ) can improve outcomes remains unknown. Methods We conducted an investigator-initiated, single-centre, open-label, parallel-group, randomised controlled trial ( ClinicalTrials.gov identifier NCT03265405 ). Consecutive subjects with pulmonary sarcoidosis were randomised (1:1) to receive either high-dose (40 mg·day −1 initial dose) or low-dose (20 mg·day −1 initial dose) oral prednisolone, tapered over 6 months. The primary outcome was the frequency of relapse or treatment failure at 18 months from randomisation. Key secondary outcomes included the time to relapse or treatment failure, overall response, change in forced vital capacity (FVC, in litres) at 6 and 18 months, treatment-related adverse effects and health-related quality of life (HRQoL) scores using the Sarcoidosis Health Questionnaire and Fatigue Assessment Scale. Findings We included 86 subjects (43 in each group). 42 and 43 subjects completed treatment in the high-dose and low-dose groups, respectively, while 37 (86.0%) and 41 (95.3%), respectively, completed the 18-month follow-up. 20 (46.5%) subjects had relapse or treatment failure in the high-dose group and 19 (44.2%) in the low-dose group (p=0.75). The mean time to relapse/treatment failure was similar between the groups (high-dose 307 days versus low-dose 269 days, p=0.27). The overall response, the changes in FVC at 6 and 18 months and the incidence of adverse effects were also similar. Changes in HRQoL scores did not differ between the study groups. Interpretation High-dose prednisolone was not superior to a lower dose in improving outcomes or the HRQoL in sarcoidosis and was associated with similar adverse effects.
Defining trajectory in severe asthma: can it be changed?
Authors: Inês Farinha, Liam G. Heaney
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>Four trajectories towards developing severe asthma have been identified, suggesting different patterns of progression of severity. This may support the need for targeting patients at high risk of progression and to provide early management strategies.</b>https://bit.ly/44alkqL
Quality over quantity: the next ACT in airway clearance in cystic fibrosis
Authors: Lisa Morrison, Christina S. Thornton
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>Airway clearance techniques (ACTs) in cystic fibrosis, while important, have been marked with few evidence-based trials. A recent study in <i>ERJ</i> is one of the first to show evidence and the importance of quality of ACT in achieving clinical outcomes.</b>https://bit.ly/3E88U82